- 學位論文
達托黴素於萬古黴素抗藥性腸球菌菌血症的治療應用
Daptomycin for the treatment of vancomycin-resistant enterococcal bloodstream infection
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摘要
利奈唑胺linezolid是目前唯一被核可，可治療萬古黴素抗藥性腸球菌vancomycin-resistant enterococci (VRE)的抗生素，不過利奈唑胺的缺點是它屬於抑菌型抗生素。達托黴素daptomycin對於萬古黴素抗藥性腸球菌有很好的殺菌效果，但是目前尚未被核可用於萬古黴素抗藥性腸球菌的治療。我們的假說是達托黴素能做為萬古黴素抗藥性腸球菌菌血症的有效治療抗生素，而達托黴素的治療效果會受到達托黴素劑量及合併乙內醯胺類抗生素的影響。首先，我們先進行系統性回顧及統合分析，以了解達托黴素用於治療萬古黴素抗藥性腸球菌菌血症的現狀。其次，我們在2010-2015年間進行了一個前瞻的觀察性世代研究，進一步了解病患使用達托黴素治療萬古黴素抗藥性腸球菌菌血症的預後。 我們利用PubMed、EMBASE及Cochrane Library搜尋在2014年1月1日前發表，有關萬古黴素抗藥性腸球菌菌血症治療的研究。經篩選，共有13個研究符合篩選條件，其中有523位病患接受達托黴素及656位病患接受利奈唑胺治療。相較於使用利奈唑胺的病患，使用達托黴素的病患有較高的死亡勝算比(odds ratio [OR], 1.43; 95%信賴區間confidence interval [CI], 1.09–1.86; P=.009)。在八個有報告調整勝算比adjusted OR (aOR)的研究做次群組分析，結果也顯示使用達托黴素的病患有較高的死亡勝算比(OR, 1.59; 95% CI, 1.02–2.50; P=.04)。 我們收集了112位使用達托黴素治療萬古黴素抗藥性腸球菌菌血症，且有臨床預後可以評估的病患。多變數迴歸顯示達托黴素劑量≥9 mg/kg相較於達托黴素劑量<7 mg/kg (aOR, 10.57; 95% CI, 2.25–49.62; P=.003)及達托黴素劑量7–9 mg/kg (aOR, 5.01; 95% CI, 1.14–21.98; P=.03)有顯著較佳的存活。我們收集了212位使用達托黴素(n=141)或利奈唑胺(n=71)治療萬古黴素抗藥性腸球菌菌血症的病患。我們發現使用利奈唑胺(aOR, 0.36; 95% CI, 0.17–0.79; P=.01)及使用高劑量達托黴素(≥9 mg/kg) (aOR, 0.26; 95% CI, 0.09–0.74; P=.01) 相較於低劑量達托黴素(6–9 mg/kg)有顯著較低的死亡率。但是使用利奈唑胺相較於使用高劑量達托黴素並沒有死亡率上的優勢(aOR, 1.40; 95% CI, 0.45–4.37; P=.57)。我們收集了114位使用達托黴素治療萬古黴素抗藥性腸球菌菌血症來評估合併乙內醯胺類抗生素使用對預後的影響。有87位病患(76.3%)有接受達托黴素合併乙內醯胺類抗生素使用。相較於單獨使用低劑量達托黴素(調整危險比adjusted hazard ratio [aHR], 5.16;95% CI, 1.34–19.89; P=.02)，使用低劑量達托黴素合併乙內醯胺類抗生素(aHR, 5.39; 95% CI, 1.62–17.93;P=.006)，及單獨使用高劑量達托黴素(aHR, 19.01; 95% CI, 2.96–121.95; P=.002)，高劑量達托黴素合併乙內醯胺類抗生素有最佳的病患存活率。我們收集了108位使用達托黴素(n=78)或利奈唑胺(n=30)治療萬古黴素抗藥性腸球菌菌血症的病患，用以做為血液中菌量的追蹤。我們使用即時定量聚合酶鏈鎖反應定量血中菌量。我們發現較慢的血中菌量清除速度（log10 copies/mL/day）和較高的死亡率有顯著的相關(aOR, 3.21; 95% CI, 1.03–10.02; P=.045)。相較於使用低劑量達托黴素，利奈唑胺(–0.04 vs. –0.41; P<.001)，及高劑量達托黴素(–0.04 vs. –0.56; P=.043)有顯著較佳的血中菌量清除速度。 在目前的統合分析中，我們發現達托黴素相較於利奈唑胺有較高的死亡率。因為納入統合分析的研究都是小規模的回溯性研究，而且達托黴素的使用劑量可能不足，所以統合分析的結果要小心的解讀。在萬古黴素抗藥性腸球菌菌血症的臨床觀察中我們發現高劑量達托黴素(≥9 mg/kg)，顯然的在治療萬古黴素抗藥性腸球菌菌血症有較低的死亡率。雖然低劑量達托黴素相較於利奈唑胺有較高的死亡率，但利奈唑胺相較於高劑量達托黴素並沒有較佳的存活率。高劑量達托黴素合併乙內醯胺類抗生素可以改善病患存活率。而利奈唑胺及高劑量達托黴素相較於低劑量達托黴素有較佳的血中菌量清除速度。因此我們的結論是可以考慮使用高劑量達托黴素來治療萬古黴素抗藥性腸球菌菌血症，並考慮合併乙內醯胺類抗生素使用。
並列摘要
Linezolid, which has bacteriostatic activity, is approved for the treatment of vancomycin-resistant enterococci (VRE) infections. Daptomycin exerts bactericidal activity against VRE, but is not approved for the treatment of VRE bloodstream infection (BSI). We hypothesize that daptomycin can be used as an effective antimicrobial agent for the treatment of VRE-BSI, and that daptomycin dose and beta-lactam combination therapy may affect the outcome of daptomycin treated VRE-BSI. We therefore performed a systematic review and meta-analysis followed by a prospective observational cohort study in 2010–2015. PubMed, EMBASE, and the Cochrane Library were searched for studies on the treatment of VRE-BSI published prior to January 1, 2014. Thirteen studies (532 patients receiving daptomycin, 656 patients receiving linezolid) met the selection criteria. Mortality was higher in patients receiving daptomycin treatment (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.09–1.86; P=.009). Subgroup analysis of eight studies that reported adjusted odds ratios (aORs) indicated that daptomycin treatment was associated with a higher mortality rate (OR, 1.59; 95% CI, 1.02–2.50; P=.04). We included 112 patients treated with daptomycin for VRE-BSI, with evaluable clinical outcomes. The best outcomes were associated with a daptomycin dose of ≥9 mg/kg compared with doses of <7 mg/kg (aOR, 10.57; 95% CI, 2.25–49.62; P=.003) and 7–9 mg/kg (aOR, 5.01; 95% CI, 1.14–21.98; P=.03). We included 212 patients treated with daptomycin or linezolid for VRE-BSI (daptomycin, n=141; linezolid, n=71). Logistic regression showed that linezolid (aOR, 0.36; 95% CI, 0.17–0.79; P=.01) and high-dose daptomycin (≥9 mg/kg) (aOR, 0.26; 95% CI, 0.09–0.74; P=.01) independently predicted lower mortality compared with low-dose daptomycin (6–9 mg/kg). Linezolid was not superior to high-dose daptomycin in terms of mortality (aOR, 1.40; 95% CI, 0.45–4.37; P=.57). We included 114 patients who received daptomycin for VRE-BSI to evaluate the effect of beta-lactam antibiotic (BLA) combinations. Of these, 87 (76.3%) received daptomycin+BLA. Patients receiving high-dose daptomycin+BLA independently had better survival than those receiving low-dose daptomycin alone (adjusted hazard ratio [aHR]=5.16), low-dose daptomycin+BLA (aHR=5.39), and high-dose daptomycin alone (aHR=19.01) (P<.05 for all comparisons). We included 108 patients with VRE-BSI for real-time quantitative polymerase chain reaction analysis of in vivo bacterial load. Slower early bacterial clearance (aOR, 3.21; 95% CI, 1.03–10.02; P=.045) independently predicted mortality. Compared with the bacterial clearance of low-dose daptomycin, linezolid and high-dose daptomycin produced rapid bacterial clearance (log10 copies/mL/day; −0.04 vs. −0.41; P<.001, and −0.04 vs. −0.56; P = .043; respectively). The current meta-analysis shows that linezolid treatment for VRE-BSI was associated with a lower mortality than daptomycin treatment. This result should be interpreted cautiously, however, because of limitations inherent to retrospective studies of small sample size and the high heterogeneity among the studies. High-dose daptomycin (≥9 mg/kg) was associated with lower mortality in patients with VRE-BSI. Despite having a lower mortality compared with low-dose daptomycin, linezolid conferred no survival benefit compared with high-dose daptomycin. High-dose daptomycin and BLA combination therapy might improve survival. High-dose-daptomycin and linezolid use were associated with rapid bacterial clearance compared with low-dose daptomycin. Our results thus suggest that high-dose daptomycin and BLA combination therapy might be an appropriate regimen for the treatment of VRE-BSI.
參考文獻
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